Stimulant-induced excitatory and inhibitory dopamine receptor signaling and trafficking

兴奋剂诱导的兴奋性和抑制性多巴胺受体信号传导和运输

基本信息

批准号：
10734322
负责人：
Christin Y. Sander
金额：
$ 69.67万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734322
关键词：
Acute Address Affect Amphetamines Animal Model Behavior Brain Chronic Complex Data Development Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Dopamine Uptake Inhibitors Drug Addiction Drug Exposure Drug Kinetics Drug Sensitization Drug abuse Drug usage Drug user Equilibrium Evolution Experimental Designs Exposure to Functional Magnetic Resonance Imaging Goals Hour Image In Vitro Injections Knowledge Lead Maintenance Measures Membrane Methodology Methods Molecular Multimodal Imaging Neurobiology Neuropharmacology Outcome Pathogenesis Pharmaceutical Preparations Play Positron-Emission Tomography Prevention Raclopride Receptor Signaling Recovery Recycling Reporting Ritalin Role Sensory Receptors Signal Transduction Stimulant Substance Use Disorder Synapses Testing Time addiction antagonist dopamine system dopamine transporter extracellular imaging study in vivo innovation insight neurobiological mechanism neuroimaging nonhuman primate pharmacologic prevent psychostimulant radiotracer receptor receptor internalization receptor recycling response stimulant abuse stimulant exposure stimulant use timeline trafficking translation to humans uptake

项目摘要

Project Summary The dopamine system plays a major role in the pathogenesis of substance use disorders. Stimulant drug use and abuse lead to several dopaminergic alterations that contribute to the complex behavior associated with the formation of addiction. A single acute exposure to a stimulant drug can trigger receptor internalization as an early synaptic adaptation mechanism to high dopamine concentrations. These mechanisms have been shown to affect neuroimaging outcomes, specifically positron emission tomography (PET), which has revealed paradoxically long reductions in dopamine D2/D3 receptor availability after stimulant-induced dopamine release. To date, we still have a limited understanding of the timeline of dopamine receptor internalization and recovery with repeated drug exposure and how these adaptation mechanisms affect whole-brain signaling of both excitatory D1 and inhibitory D2-type receptors. This study aims to address this knowledge gap by characterizing how two classes of stimulant drugs (amphetamine and methylphenidate) modulate dopamine receptor subtype signaling and receptor trafficking over time. Using state-of-the-art simultaneous PET and functional magnetic resonance imaging (fMRI) methodology in non-human primates, the timescales of amphetamine-induced receptor internalization and recycling will be established using repeated amphetamine administrations. Targeted dopaminergic blocking drugs will be paired with amphetamine to determine how the balance between excitatory D1 and inhibitory D2 receptor signaling and trafficking is modulated over time. The effects of repeated amphetamine will then be compared to those of methylphenidate to assess varying levels of dopamine surges and differential mechanisms of action across these two stimulant drugs. Overall, this study will unravel brain- wide molecular and functional changes due to repeated stimulant drug exposure by imaging the timescales of dopamine receptor trafficking in the living brain in a translational animal model. The results will elucidate the role of dopamine D1 and D2-type receptor adaptations, thereby providing important insight into the neurobiological mechanisms involved in repeated stimulant drug use relevant for initiating and eventually preventing drug sensitization and addiction.

项目概要多巴胺系统在物质使用障碍的发病机制中发挥着重要作用。使用兴奋剂和滥用会导致多种多巴胺能的改变，从而导致与多巴胺相关的复杂行为成瘾的形成。单次急性暴露于兴奋剂药物可以触发受体内化作为早期高多巴胺浓度的突触适应机制。这些机制已被证明可以影响神经影像学结果，特别是正电子发射断层扫描（PET），它揭示了矛盾兴奋剂诱导的多巴胺释放后，多巴胺 D2/D3 受体的可用性长期减少。迄今为止，我们对多巴胺受体内化和恢复的时间线仍然有有限的了解药物暴露以及这些适应机制如何影响兴奋性 D1 和 D1 的全脑信号传导抑制性 D2 型受体。本研究旨在通过描述两个类别如何解决这一知识差距兴奋剂药物（苯丙胺和哌醋甲酯）调节多巴胺受体亚型信号传导和随着时间的推移受体贩运。使用最先进的同步 PET 和功能磁共振非人类灵长类动物成像（fMRI）方法，安非他明诱导受体的时间尺度将通过重复使用安非他明来建立内在化和循环利用。有针对性多巴胺能阻断药物将与安非他命配对，以确定兴奋性和兴奋性之间的平衡如何 D1 和抑制性 D2 受体信号传导和运输会随着时间的推移而受到调节。重复的效果然后将安非他明与哌醋甲酯进行比较，以评估不同水平的多巴胺激增以及这两种兴奋剂药物的不同作用机制。总的来说，这项研究将揭示大脑通过对药物的时间尺度进行成像，可以发现由于重复接触刺激性药物而导致的广泛的分子和功能变化转化动物模型中活体大脑中多巴胺受体的贩运。结果将阐明其作用多巴胺 D1 和 D2 型受体适应，从而提供对神经生物学的重要见解涉及重复使用刺激性药物的机制，与引发和最终预防药物相关致敏和成瘾。